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    Role of cytoskeletal proteins in microvascular mechanotransduction

    Role of cytoskeletal proteins in microvascular mechanotransduction

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    Laurent Loufrani

    Photo Laurent Loufrani

    Team members : 

    • Laurent Loufrani, Ph.D.
    • Frédérique Pinaud, M.D., Ph.D.
    • Olivier Fouquet, M.D., Ph.D.
    • Linda Grimaud, assistant-engineer
    • Tristan Champin, PhD Student
    • Pauline Robert, PhD Student

    Resistance arteries represent the majority of the vascular tree. In these vessels, pressure induces a contraction (myogenic tone) and flow (shear stress) a dilation. In physiological conditions pressure and flow-dependent tone interact to allow blood flow regulation in downstream located tissues. In pathological situations (hypertension, diabetes or myopathies…), blood flow is not efficiently controlled with dramatic consequences. In cytoskeletal deficiency, we found strong changes in flow-dependent dilation in arteries from mice lacking vimentin, desmin or dystrophin. These vascular defects are associated to a deficiency in microvascular remodeling after chronic changes in blood flow. Thus it is now important to determine the consequences of these vascular disorders related to changes in cytoskeletal proteins arrangement, as well as the exact role of these proteins in the mechanotransduction (pressure and flow) pathways in the microcirculation. Flow-related transduction pathways in resistance arteries will be studied in acute (flow-mediated dilation) and chronic conditions (remodeling), in physiological and pathological situations. Furthermore, our team is also studying the involvement of circulating cells (macrophages, neutrophil cells, platelets…) in the microcirculation (inflammation, remodeling…)

    Our team use molecular biology, biochemistry, or confocal and intravital microscopy. Physiological aspects are also studied with arteriographs allowing the control of pressure and flow in isolated resistance arteries in vitro. Changes in diameter in response to flow (vasodilation) or pressure (contraction) will be correlated to the activation of proteins potentially involved in the response: integrins, adhesion molecules such as PECAM or P-selectin, dystrophin, δ-sarcoglycan, caveolin or filamin. Those signaling pathways will be studied in culture cells, control animals and in mice lacking a protein.


    Chronic changes in blood flow will be induced locally in mesenteric resistance by microsurgery. In  parallel, human arteries will be used in areriographs and organ-culture myograph in order to validate in humans the pathways discovered in mice arteries.

    This study will open new therapeutic ways in the pathological situations involving mutations in the proteins involved in the pathways investigated, as well as in other diseases involving the microcirculation which remains minimally studied, by contrast to the large amount of diseases involving mainly the microcirculation.

     

    Collaborations :

    CHU Angers, France

    Institut du thorax, INSERM915, Nantes, France

    Le Paris-Centre de recherche Cardiovasculaire (PARCC), Paris , France

    Centre de Recherche des Cordeliers, Paris, France

    AFM, Paris, France

    Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Allemagne

     

    Research articles :

    •  Loufrani L, Matrougui K, Gorny D, Duriez M, Blanc I, Lévy BI, Henrion D. Flow (shear stress)-induced endothelium-dependent dilation is altered in mice lacking the gene encoding for dystrophin. Circulation 2001; 103:864-870.
    •  Loufrani L, Matrougui K, Li Z, Lévy BI, Lacolley P, Paulin D, Henrion D. Selective microvascular dysfunction in mice lacking the gene encoding for Desmin. FASEB Jrong>&nbs. 2002n/presenta:117-119/ul>
      •  Li L, Matroug&eacutD, Henrione;vy BI, Henrion D. Flow (sExly")rovaMcular dysfuncAdap in th lar in diameteBow wiFisolateMkingLthe gene enGodinE for Desmin. FASEB JAraphs sclsige lb stituBal g> 2001; 103:2; 22:1579-84/ul>
        •  Li L, Matroug&;vy BI, Henrion D. Flow (sDare arovascular remodeladap in th lar changes in blood flow. Thus e lacking the genDin. << 2001; 1tio.sabi/strong>

          •  L (sYouPhD StuL.ni, Ph.D.Circulation

            •  Li L, MatrougDublata C Lévy BI, LacolleD, Henrion D. Selectil waabsf theasesin. e lackingmiccontrNOent dilatior remodeln in mic: larosche in mychronicaIn tat circterioivatisp;, cavosidencodtispcin<. 2002n/pAraphs sclsige lb stituBal g> 2001; 103:4 Apr;24(4):671-6/ul>
              •  LiLoufrani, Ph.D. loolow. Thus e lacdxackingmie arteries will be s INuior remodelwudiling after corelium-dependon isToTracms iof cirCirculaJ.Hsion, diabeg> 2001; 103:5 o ar23(10):1855-6
              •  LBabsp-Menguy C LBoc.D., A D,uiho, Aoug inpl, drionAmio, MJonA-1-itohhe a R, i L, Matroug D. Select001; 1Efre assaser arteracpolyphen smawayso>&nsry, oceraar remode chartFASEB Jrong>&nbs. 2002n/pres7 Nov;21(13):3511-21/ul>
                •  Li L, MatrougR/con neauZ, LBoc.D., A DDumnty O l-Akttrashear stress) a dilatstance arteries will bFASEB JAm Jlogical Drch"tionlogical bs. 2002n/pres8 Apr;294(4):H1906-13/ul>
                  •  Li L, Matroug D. SelectiRthese proteletal protpre lahear stress) a dilad endothen) or prean-cing after cstance arteries will bFASEB J (MuBal nE giermputbs. 2002n/pres8 Feb 2/ul>
                    •  L,uilluy C LRthliuumend-valtheM, i L, MatrougBo In; Angers" ug D. Selec, Sonsudhe oug&oi)).r GleD,caud Ptivte20d transdue g> l SLK phosphoryranssiver188se pRhoA lar endotoation) or pre lae to flow (vn bit, dian II Tsio 2che eptoryion of proCirculationsabibs. 2002n/pres8 Mayr23;102(10):1265-74/ul>
                      •  Lhis if-Navoli R, Folraner cJHleBain., ez M,es d F,t LouitzthelleArhatteeM, Jodss)M, DederieAug inttraan FC LSchu6]> UugR/con neauZ, Li L, MatrougPnttreAugSachs F,tumlmM orugP ress DJonHonoe;d&eacut E.Polycin.in-1ean-c-2fdo not ion in eure and flos diangCirculatin .g> 2001; 103:9 O ar30;139(3):587-96/ul>
                        •  LCousiheM, C">&aud MAugBabsp-Menguy C LTNuiaan B DDumnty O l patFisolateR d Mic resistance arterieA.

                           2/pre10 Jan;55(1):109-/li>>

                          •  LR/con neauZ, LBfterherc in tem;ne et ShesEJug innoeracS l 2entrithe tge lbox me A2gmicconvn bit, dian II tsio 2che eptoryatio traxn downstre or mstan d nce arteries will bFASEB JHsion, diabeg> 2/pre10 Feb;55(2):339-44/ul>
                            •  LBfterherc in tem;ne et ShesEJugVy")r;ne et Sr&eaEug,uiho, AougTNuiaan B De L, Matroug D. SelectiCycow.xyone> l-2f the rv miciated dilatioing aftter cstaold obteinZucknicn d ric resistas will bFASEB Jasculaire sabibs. 2002n/pre10 Jun 1;86(3):516-25/ul>
                              •  L,uilluy C LBe;d&eacutgeeleJugTNueri1>-1z GleRthliuumend-valtheM, R/con neauZ, Li L, Matroug D. Selec, Scalbsp;aEugBrireAugTed ts RM, OfrererinscSFASEB JN d Midg> 2/pre10 Feb;16(2):183-9
                              •  LNguytheDinh Ca, A D, Sel- inrhacut V Li L, MatrougLaba, C LBenjisp;rougFareri Nley P, Paulin D. Selec, Jaissuet,til walium-depeoscopne huoco&nbsoidche eptoryion in eurtioence acceo In flushedlow. Te (contr< rong>&n/pre10 Jul;24(7):2454-63/ul>
                                •  LBusryerinellePll beAugStsi-Rekowska B DHn nme(trur Pug&oL, Matroug D. Selec, Shi Y DDuelsne " ug oererelleGatzke NleWn bdHleyeyerine, LUlmrougRom/?sacutHaufflin befochuk R, Djonov V Lvri VetheT,f duNob du,tiPulsn d dutress)).r Gja5/g a in eas willoscier" /tyean-cing after cea>FASEB JDea>lop cir 2001; 10310 Jul;137(13):2187-96/ul>
                                  •  LBabsp-Menguy C LTNuiaan B DCousiheM, Dumnty O&aud MAuge L, Matroug D. SelectiIent of circulaa bit, dian II pathwaying after cstndotherasa changesde" /> l patlow. Thus e lan d ric resistance arteries will bFASEB JHsion, disabibs. 2002n/pre10 Aug;33(8):857-66/ul>
                                    •  L M.D., F,t L, MatrougTNuiaan B Deambsp;ac, Van-eknickhoovaoug D. Selec, BaufrotpreCtoskeChangns invc proteinr remodeln in micice laoxn hurova a dil mice lion, remoderaspulsn d /tyestance arteries will bFASEB JJsignracvasculaire gSurgbs. 2002n/pre11 Nov;142(5):1254-62/ul>
                                      •  LBftezna C L& L, MatrougSubla JFugGor DeM, Jodiedin Vinvcoc. OFASEB JAutoimmun Revbs. 2002n/pre11 Jul;10(9):559-62/ul>
                                        •  LBftezna C L& L, MatrougSubla JFugGor DeM, Jodiedin Vinvcoc. OFASEB JAutoimmun Revbs. 2002n/pre11 Jul;10(9):559-62/ul>
                                          •  LFreidja MougTnrhoun Z, LTNuiaan B DFLssot-Lucht C L& L, Matroug D. Selectil waAGE-umbFASEB JD or myobs. 2002n/pre12i>>
                                            •  LR/con neauZ, LTNuiaan B DGalmain. GleFLssot C Lhis if-Navoli R, Kauff dinvol GleMsistskayeM, Dues d F,t, assisrougue ineJugLscueux AugPiz, drAugBaunrie V LJeunminiRechXleF039;R, G&oolekseasneJRley P, Paulin D. Selec, Leacute L, Matrotive microvament of circulasueumae to flowfaa>FASEB JAraphs sclnicige lb stituBal g> 2/pre13 Feb;33(2):339-46ul>
                                              •  L,almain. GleLaba, C LMsistskayeM, Ai, AissaZ, LB L&eaJugR/con neauZ, LBourhimeM, Csourtiec, i L, Matro DGao-LeaJleF039;R, inllan-elin D. Selec, DecivanJFugRegnCont V Li P, Paulin Leactoskion of proteinSueumaR to flowFaa> l V remodelMuremodelT flushedA willoscStiffndil ateMkinCirculationsabibs. 2002n/pre13 Febpre/ul>
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